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The table of evidence regarding inflammatory and even autoimmune processes in Alzheimer's continues to accumulate in a piecemeal fashion, awaiting theoretical frameworks and experimental breakthroughs to give it direction and a greater following (see ARF related news story). But accumulate it does, and in this article we summarize some of the recent appetizers.

Converging on an Age-of-Onset Player

A report from Yi-Ju Li, Margaret Pericak-Vance, and their colleagues at Duke University in Durham, North Carolina, has recently received a great deal of press attention. Following up on their report last year of a locus on chromosome 10q that influences age of onset for both Alzheimer's and Parkinson's disease (see ARF related news story), the researchers have applied a strategy they call "genomic convergence" to pull some genes of interest out of this region. (10q, of course, is the hottest region of additional suspected AD genes.)

As reported in the October 21 issue of Human Molecular Genetics, gene expression studies of hippocampal tissue revealed four genes in this region that differed in expression levels between AD patients and controls: stearoyl-CoA desaturase; NADHubiquinone oxidoreductase 1 β complex 8; protease, serine 11; and glutathione S-transferase, ω-1 (GSTO1). Only the last, along with its neighbor GSTO2, turned out to show a significant association with age-of-onset for AD or PD in an allelic association study. There was no evidence that either of the genes was associated with disease risk.

Glutathione S-transferases play roles in the transformation of many drugs, carcinogens, and products of oxidative stress (for more information, consult the OMIM page on GSTO1). Interestingly, GSTO1 is expressed in glial cells (Board et al., 2000) and may be involved in the posttranslational modification of the proinflammatory cytokine interleukin 1β (IL-1β). This proposition arises from evidence that a group of experimental compounds that inhibit the release of cytokines act by inhibiting the processing of IL-1β (Laliberte et al., 2003).

Given that IL-1β release is a well-accepted marker for inflammatory microglial activation, plus findings that IL-1β is overexpressed both in AD and PD brain, it is worth exploring whether targeting GSTO1 would be an effective way to inhibit inflammation, and possibly prevent neurodegeneration in Alzheimer's, conclude the authors.

The Inflammation That Didn't Go Away

A study in the November issue of the Annals of Neurology, led by Pat McGeer of the University of British Columbia in Vancouver, Canada, demonstrates the troubling staying power of inflammatory reactions in the central nervous system in an animal model of Parkinson's disease. As in AD, use of nonsteroidal antiinflammatory drugs (NSAIDs) has been found to correlate with a reduced risk of PD. (And as the authors mention, the occurrence of the particular allele of IL-1β that results in expression of the proinflammatory cytokine is higher in both PD and AD patients than in controls (see ARF related news story).

McGeer's team followed up on evidence that parkinsonism in patients exposed to the toxin MPTP is accompanied—even years after the exposure—by neural inflammation. The researchers examined the brains of monkeys who had been exposed to MPTP 10-14 years earlier in all but one case. The monkeys experience a progressive form of parkinsonism. At autopsy, along with the characteristic loss of substantia nigra neurons, the researchers found highly activated microglia. The degree of neuronal degeneration paralleled the intensity of the neuroinflammatory response.

"Determining the reasons for the persisting effects in the MPTP model may provide valuable insights into the origins of PD. This could be particularly important if it reveals a route to therapy based on termination of a local inflammatory process," conclude the authors. (see ARF related news story).

Comparative Genomics

So many genes, so many possible interactions. It seems daunting to try to get a handle on the genes that might play a role in Alzheimer's and other polygenic neurodegenerative disorders. As always, nuggets of value can be found by simplifying. A second report in the October 29 Journal of Neuroscience shows the potential for identifying genes of interest by probing the genomes of animal models.

Olle Lidman of the Karolinska Institute in Stockholm, Sweden, and colleagues chose to study the "axon reaction," a relatively accessible experimental model of spinal cord axonal lesions. These lesions produce neurodegeneration in the cord, accompanied by glial activation. In this study, the researchers examined two strains of rat, which proved to have very different responses to the experimental manipulation.

Denervated motor neurons in the PVG (RT1c) strain had 36 percent greater survival at two weeks post-lesion than did DA(RT1avl) rats. Compared to the PVG rats, DA rats had sevenfold greater T cell infiltration into the cord, increased glial activation, and a whopping 10-fold higher expression of major histocompatibility complex class II genes.

The researchers then analyzed the F2 generation of crosses between the two strains to look for gene loci that might play a role in these neurodegenerative and neuroimmune responses. Their key finding was that relatively few, discrete loci containing genes polymorphic between the strains appear to control the different aspects of the axon reaction. For both neurodegeneration and T cell influx, two gene loci displayed linkage; a single locus on chromosome 10 displayed extreme linkage to MHC complex II expression on microglia. It will be fascinating to see if this multipronged approach can be applied to animal models of Alzheimer's and other genetically complex neurodegenerative diseases.

In Search of NSAID Targets

The epidemiologic data pointing to a protective effect of NSAIDs in AD have been reinforced by experimental data: e.g., NSAIDs have reduced both behavioral deficits and amyloid deposition in APP transgenic mice (Lim et al., 2001; 2000). This dovetails nicely with evidence that inflammatory cytokines increase secretion of Aβ in vitro (Blasko et al., 1999; 2000), though clinical trials so far have been largely disappointing. Meanwhile, scientists are trying to work out the question through which targets NSAIDs might be acting to decrease Aβ deposition. One candidate is the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ). (For an in-depth discussion, see ARF forum).

PPARγ inhibits the expression of proinflammatory genes and protects neurons, and PPARγ agonists protect neurons in an MPTP mouse model of Parkinson's (Breidert et al., 2002). In vitro, NSAIDs have been shown to bind and activate PPARγ's transcription regulatory activity.

In the October 29 Journal of Neuroscience, Michael Heneka of the University of Bonn in Germany and colleagues have examined the relationship between NSAIDs and PPARγ in neuroblastoma cells stimulated by cytokines, which induce the cells to secrete Aβ. Counter to many previous results, write the authors, this did not appear to be attributable to increased APP expression, but rather to a direct effect on APP processing. BACE1 was identified as a suspected target because cytokines raised BACE expression, activity, and mRNA levels. (The researchers found no evidence that proinflammatory cytokines act on γ-secretase-mediated APP processing.)

Treatment with either the NSAIDs ibuprofen or indomethacin, or a PPARγ agonist, downregulated Aβ secretion by reducing BACE1 expression and activity. "Our work…indicates the existence of a vicious cycle that accelerates the development of AD, because amyloid peptides cause microglial activation and astrocytosis and, therefore, increased secretion of a number of cytokines. These cytokines may subsequently upregulate BACE1 expression and increase Aβ generation…." write the authors (see ARF related news story); ARF news story).

Regarding the finding that ibuprofen reduces Aβ production, the authors propose that it is primarily mediated by PPARγ. Others focus on an effect through γ-secretase modulation (see, for example, Eriksen et al., 2003).—Hakon Heimer